This invention relates to antiparasitic formulations, particularly antiparasitic formulations containing avermectins or milbemycins, including derivatives thereof, suitable for topical application to mammals, including humans and domestic animals such as cats and dogs, and which are useful in the treatment of conditions caused by endo- and/or ectoparasites. Especially of interest are formulations of substances active against fleas and/or heartworms.
Antiparasitic avermectins, milbemycins and their derivatives have been described in numerous publications, see for example European Patent Applications publication nos. 0 214 731, 0 284 176, 0 317 148, 0 308 145, 0 340 832, 0 335 541, 0 350 187, 0 170 006, 0 254 583, 0 334 484, 0 410 615, British Patent Application numbers 1 573 955, 1 390 336, International Patent Applications publication nos. WO 94/15944 and WO 95/22552, xe2x80x9cIvermectin and Abamectinxe2x80x9d, W C Campbell, Springer Verlag, New York (1989), and xe2x80x9cDoramectinxe2x80x94a potent novel endectocidexe2x80x9d, A C Goudie et al, Vet.Parasitol. 49 (1993)5.
A number of such substances have been developed for commercialisation, for example ivermectin (Ivomec(trademark)), doramectin (Dectomax(trademark)), moxidectin and abamectin (Avomec(trademark)).
International Patent Application publication no. WO 94/15944, the teaching of which is herein incorporated by reference in its entirety, describes a family of 5-oximino derivatives of avermectin 13-monosaccharides having activity in the treatment of a number of conditions caused by endo- and/or ectoparasites, including 5-oximino22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide (selamectin, Example 5).
We describe herein long-acting formulations suitable for topical application that are capable of delivering avermectins and milbemycins with activity against endo- and/or ectoparasites. These formulations have good cosmetic profiles, stability on storage, cutaneous tolerability, and transdermal delivery characteristics.
According to one aspect of the invention there is provided a long-acting antiparasitic formulation suitable for topical application including:
(a) about 0.1-50% w/v an avermectin or milbemycin having activity against endo- and/or ectoparasites;
(b) about 1-50% v/v a di(C2-4 glycol) mono(C1-4 alkyl) ether;
(c) optional antioxidant; and
(d) an optional skin acceptable volatile solvent q.s. v/v.
By xe2x80x9cw/vxe2x80x9d is meant weight/volume, i.e. xe2x80x9c1% w/vxe2x80x9d means 1 g in 100 ml of the formulation.
The formulations of the invention have a good cosmetic profile. For instance when applied topically to the fur of a domestic animal such as a cat or dog, they spread well giving good skin contact across a wide range of temperatures. They do not leave an unsightly oily patch, of the type associated with some commercial avernectin or milbemycin formulations in fatty excipients.
Certain of the formulations according to the invention are effective enough to enable long periods, e.g. a several weeks or a month, between treatments.
Preferably the active compound has activity against both endo- and ectoparasites.
Preferably the active compound is selected from ivermectin, doramectin, abamectin, moxidectin, and the avermectin 13-monosaccharide 5-oximes generically and specifically disclosed in International Patent Application publication no. WO 94/15944.
Most preferably the active compound is 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide (selamectin).
Preferably the di(C2-4 glycol) mono(C1-4 alkyl) ether is diethylene glycol monomethyl ether (DEGMME) or dipropylene glycol monomethyl ether (DPGMME).
More preferably the glycol monomethyl ether is DPGMME.
Any source of pharmaceutical/veterinary quality di(C2-4 glycol) mono(C1-4 alkyl) ethers may be used. For instance, an acceptable commercial source of DPGMME is Dow Corning, whose product xe2x80x9cDowanol DPM(trademark)xe2x80x9d has the following characteristics: B.pt. 74.6xc2x0 C. at 13 mbar, freezing point xe2x88x9283xc2x0 C., density 0.948 g/cm3 at 25xc2x0 C., viscosity 3.72 mPas at 25xc2x0 C. and refractive index of 1.421 at 25xc2x0 C.
Preferably the di(C2-4 glycol) mono(C1-4 alkyl) ether is present in the formulation at a level of up to about 20% v/v, yet more preferably in the range about 2-16% v/v, further more preferably in the range about 4-12% v/v, and most preferably in the range about 6-12% v/v.
Preferably the skin acceptable volatile solvent is present and is ethanol or isopropanol (IPA).
More preferably the skin acceptable solvent is IPA.
Preferably the w/v to v/v ratio of active compound to the glycol monomethyl ether is in the range about (0.5 to 2) to 1.
More preferably the w/v to v/v ratio of active compound to the glycol monomethyl ether is about (0.7 to 1.4) to 1.
Yet more preferably the w/v to v/v ratio of active compound to the glycol monomethyl ether is about (0.9 to 1.1) to 1.
Most preferably the w/v to v/v ratio of active compound to the glycol monomethyl ether is about 1:1.
Preferably the level of active avermectin or milbemycin in the total formulation is in the range about 1% to about 16% w/v, more preferably about 4% to about 12% w/v, yet more preferably about 6 to about 12% w/v.
Optionally the formulation can further include an antioxidant, such as propylgallate, BHA (2-t-butyl-4-methoxyphenol), or BHT (2,6-di-t-butyl-4-methylphenol).
Preferably, the antioxidant, if present, is BHT.
Preferably, the antioxidant, if present, is at a level of less than 0.2% w/v, more preferably less than 0.1% w/v.
Preferably the formulation consists of:
(a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide (selamectin, at a level of 1% to 16% w/v);
(b) DEGMME or DPGMME at 1 to 16% v/v, and at a w/v to v/v ratio of active compound to DEGMME/DPGMME of about 1:1;
(c) isopropanol q.s. 100% v/v;
and, optionally (d) BHT (at less than 0.1% w/v).
More preferably the formulation consists of:
(a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide (selamectin, at a level of 6% to 12% w/v);
(b) DEGMME or DPGMME 6 to 12% v/v, and at a w/v to v/v ratio of active compound to or DEGMME/DPGMME of about 1:1;
(c) isopropanol q.s. 100% v/v;
and, optionally (d) BHT (at less than 0.1% w/v).
A preferred group of formulations consists of the formulations mentioned in the Examples below.
Another aspect of the invention is a method of treatment of a condition caused by an endo- or ectoparasite by administration of an effective amount of a formulation according to the invention.
Another aspect of the invention is a formulation according to the invention for use in medicine.
Another aspect of the invention is the use of a formulation according to the invention in the manufacture of a medicament for the treatment of conditions caused by endo- and/or ecto-parasites.
Formulations according to the invention can be made by standard methods, for example by dissolution of the avermectin and/or milbemycin and optional antioxidant in the solvent or solvents, in accordance with standard pharmaceutical or veterinary practice, e.g. by agitation of a mixture of the ingredients, if necessary with concurrent warming.
The amount of antiparasitic avermectin/milbemycin material in a unit dose of the formulation can of course vary depending on the efficacy of the avermectin/milbemycin in treating the condition of interest, the desired frequency of application, etc., according to standard veterinary and pharmaceutical practice.
The formulations of the invention can be administered in a way appropriate to the specific use envisaged, the particular species and weight of host animal being treated, the parasite or parasites involved, degree of infestation, etc., according to standard medical and veterinary practice.
For example, for dogs and cats, a dose of 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide (selamectin) of between 4 mg/kg and 12 mg/kg, preferably about 9 mg/kg body weight of the host animal as a single dose once per month will be satisfactory for flea control and heartworm prophylaxis, but of course there will be instances where higher or lower dosage ranges are indicated and such are within the scope of this invention. A typical dosage regime for a 6 mg/kg dose, to a domestic animal such as a typical domestic cat or dog, would be 0.25 ml to 2 ml of the formulation of Example 1 per dose per month.
The formulations according to the invention are especially suitable to be administered topically. For topical application, dip, spray, pour-on, spot-on, jetting fluid, shampoos, collar, tag or harness may be used. Particularly preferred is a spot-on formulation.
It is to be understood that reference to treatment indudes prevention, alleviation and cure of the condition or conditions caused by the parasite or parasites.